Investigations of organic lithic micro-residues have, over the last decade, shifted from entirely morphological observations using visible-light microscopy to compositional ones using scanning ...electron microscopy and Fourier-transform infrared microspectroscopy, providing a seemingly objective chemical basis for residue identifications. Contamination, though, remains a problem that can affect these results. Modern contaminants, accumulated during the post-excavation lives of artifacts, are pervasive, subtle, and even "invisible" (unlisted ingredients in common lab products). Ancient contamination is a second issue. The aim of residue analysis is to recognize residues related to use, but other types of residues can also accumulate on artifacts. Caves are subject to various taphonomic forces and organic inputs, and use-related residues can degrade into secondary compounds. This organic "background noise" must be taken into consideration. Here we show that residue contamination is more pervasive than is often appreciated, as revealed by our studies of Middle Palaeolithic artifacts from two sites: Lusakert Cave 1 in Armenia and Crvena Stijena in Montenegro. First, we explain how artifacts from Lusakert Cave 1, despite being handled following specialized protocols, were tainted by a modern-day contaminant from an unanticipated source: a release agent used inside the zip-top bags that are ubiquitous in the field and lab. Second, we document that, when non-artifact "controls" are studied alongside artifacts from Crvena Stijena, comparisons reveal that organic residues are adhered to both, indicating that they are prevalent throughout the sediments and not necessarily related to use. We provide suggestions for reducing contamination and increasing the reliability of residue studies. Ultimately, we propose that archaeologists working in the field of residue studies must start with the null hypothesis that miniscule organic residues reflect contamination, either ancient or modern, and systematically proceed to rule out all possible contaminants before interpreting them as evidence of an artifact's use in the distant past.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Diet and parasitism can have powerful effects on host gene expression. However, how specific dietary components affect host gene expression that could feed back to affect parasitism is relatively ...unexplored in many wild species. Recently, it was discovered that consumption of sunflower (Helianthus annuus) pollen reduced severity of gut protozoan pathogen Crithidia bombi infection in Bombus impatiens bumble bees. Despite the dramatic and consistent medicinal effect of sunflower pollen, very little is known about the mechanism(s) underlying this effect. However, sunflower pollen extract increases rather than suppresses C. bombi growth in vitro, suggesting that sunflower pollen reduces C. bombi infection indirectly via changes in the host. Here, we analyzed whole transcriptomes of B. impatiens workers to characterize the physiological response to sunflower pollen consumption and C. bombi infection to isolate the mechanisms underlying the medicinal effect. B. impatiens workers were inoculated with either C. bombi cells (infected) or a sham control (un-infected) and fed either sunflower or wildflower pollen ad libitum. Whole abdominal gene expression profiles were then sequenced with Illumina NextSeq 500 technology.
Among infected bees, sunflower pollen upregulated immune transcripts, including the anti-microbial peptide hymenoptaecin, Toll receptors and serine proteases. In both infected and un-infected bees, sunflower pollen upregulated putative detoxification transcripts and transcripts associated with the repair and maintenance of gut epithelial cells. Among wildflower-fed bees, infected bees downregulated immune transcripts associated with phagocytosis and the phenoloxidase cascade.
Taken together, these results indicate dissimilar immune responses between sunflower- and wildflower-fed bumble bees infected with C. bombi, a response to physical damage to gut epithelial cells caused by sunflower pollen, and a strong detoxification response to sunflower pollen consumption. Identifying host responses that drive the medicinal effect of sunflower pollen in infected bumble bees may broaden our understanding of plant-pollinator interactions and provide opportunities for effective management of bee pathogens.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The aim of this study was to evaluate evolution of ultra-processed food intake and recurrent weight gain in patients who underwent Roux-en-Y gastric bypass.
Materials and Methods
This ...study is an observational longitudinal study that evaluated patients who underwent metabolic and bariatric surgery at four time points: before surgery and at 3, 12, and 60 months after surgery. Anthropometric and dietary intake data were collected through two 24-h dietary recalls. All foods consumed were classified according to degree of processing. Recurrent weight gain was considered the difference between current weight and nadir weight.
Results
The sample consisted of 58 patients with a mean age of 38.7 ± 8.9 years and 68% female. After 60 months, mean excess weight loss and recurrent weight gain were 73.6 ± 27.2% and 22.5 ± 17.4%. Calorie and macronutrient intake decreased significantly between the pre-surgery period, and 3 and 12 months post-surgery; however, there was no significant difference after 60 months. In relation to food groups or macronutrients, no difference was observed between the pre-surgery period and 60 months post-surgery. The contribution of unprocessed or minimally processed foods to calorie intake gradually decreased after 3 months post-surgery.
Conclusion
The profile of dietary intake after 60 months of metabolic and bariatric surgery tends to approach that of the pre-surgery period. The contribution of unprocessed and minimally processed foods to calorie intake decreased after 60 months, while ultra-processed food contribution increased.
Graphical Abstract
Since the publication of the first Asia Pacific Consensus on Colorectal Cancer (CRC) in 2008, there are substantial advancements in the science and experience of implementing CRC screening. The Asia ...Pacific Working Group aimed to provide an updated set of consensus recommendations.
Members from 14 Asian regions gathered to seek consensus using other national and international guidelines, and recent relevant literature published from 2008 to 2013. A modified Delphi process was adopted to develop the statements.
Age range for CRC screening is defined as 50-75 years. Advancing age, male, family history of CRC, smoking and obesity are confirmed risk factors for CRC and advanced neoplasia. A risk-stratified scoring system is recommended for selecting high-risk patients for colonoscopy. Quantitative faecal immunochemical test (FIT) instead of guaiac-based faecal occult blood test (gFOBT) is preferred for average-risk subjects. Ancillary methods in colonoscopy, with the exception of chromoendoscopy, have not proven to be superior to high-definition white light endoscopy in identifying adenoma. Quality of colonoscopy should be upheld and quality assurance programme should be in place to audit every aspects of CRC screening. Serrated adenoma is recognised as a risk for interval cancer. There is no consensus on the recruitment of trained endoscopy nurses for CRC screening.
Based on recent data on CRC screening, an updated list of recommendations on CRC screening is prepared. These consensus statements will further enhance the implementation of CRC screening in the Asia Pacific region.
Today computational chemistry is a consolidated tool in drug lead discovery endeavors. Due to methodological developments and to the enormous advance in computer hardware, methods based on quantum ...mechanics (QM) have gained great attention in the last 10 years, and calculations on biomacromolecules are becoming increasingly explored, aiming to provide better accuracy in the description of protein-ligand interactions and the prediction of binding affinities. In principle, the QM formulation includes all contributions to the energy, accounting for terms usually missing in molecular mechanics force-fields, such as electronic polarization effects, metal coordination, and covalent binding; moreover, QM methods are systematically improvable, and provide a greater degree of transferability. In this mini-review we present recent applications of explicit QM-based methods in small-molecule docking and scoring, and in the calculation of binding free-energy in protein-ligand systems. Although the routine use of QM-based approaches in an industrial drug lead discovery setting remains a formidable challenging task, it is likely they will increasingly become active players within the drug discovery pipeline.
In response to nutrient deprivation, the cell mobilizes an extensive amount of membrane to form and grow the autophagosome, allowing the progression of autophagy. By providing membranes and ...stimulating LC3 lipidation, COPII (Coat Protein Complex II) promotes autophagosome biogenesis. Here, we show that the F-box protein FBXW5 targets SEC23B, a component of COPII, for proteasomal degradation and that this event limits the autophagic flux in the presence of nutrients. In response to starvation, ULK1 phosphorylates SEC23B on Serine 186, preventing the interaction of SEC23B with FBXW5 and, therefore, inhibiting SEC23B degradation. Phosphorylated and stabilized SEC23B associates with SEC24A and SEC24B, but not SEC24C and SEC24D, and they re-localize to the ER-Golgi intermediate compartment, promoting autophagic flux. We propose that, in the presence of nutrients, FBXW5 limits COPII-mediated autophagosome biogenesis. Inhibition of this event by ULK1 ensures efficient execution of the autophagic cascade in response to nutrient starvation.
Labeling immune cells with zirconium-89 (
Zr)-oxine has become a viable method to track cells in vivo by PET in various pre-clinical animal models and in clinical applications. Currently,
Zr-oxine ...cell labeling is performed manually, which requires a highly trained specialist and is prone to human error. As the first phase in developing a fully automated radiolabeling system to address this problem, we assess the use of acoustophoresis cell washing to replace the centrifugal cell washing used in the current
Zr-oxine cell radiolabeling procedure. To accomplish this, a cell radiolabeling procedure was developed in which two steps requiring a centrifuge to wash cells were replaced using acoustophoresis cell washing methods. The process was tested using murine EL4 lymphoma and T cells. The centrifuge cell labeling procedure was used as a control to compare the acoustophoresis cell washing procedure. The acoustophoresis method produced radiolabeled cells with similar properties to the centrifugal method when comparing labeling efficiency, labeled specific activity, efficacy of removing unbound
Zr-oxine from the suspension, cell viability measured using annexin V/propidium iodide staining and activation function. This suggests that acoustophoresis cell washing can be used in the design of an automated benchtop, good manufacture practice-qualified acoustophoresis cell radiolabeling device.
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
Breast cancer has been redefined into three clinically relevant subclasses: (i) estrogen/progesterone receptor positive (ER+/PR+), (ii) HER2/ERRB2 positive, and (iii) those lacking expression of all ...three markers (triple negative or basal-like). While targeted therapies for ER+/PR+ and HER2+ tumors have revolutionized patient treatment and increased lifespan, an urgent need exists for identifying novel targets for triple-negative breast cancers. Here, we used integrative genomic analysis to identify candidate oncogenes in triple-negative breast tumors and assess their function through loss of function screening. Using this approach, we identify lactate dehydrogenase B (LDHB), a component of glycolytic metabolism, as an essential gene in triple-negative breast cancer. Loss of LDHB abrogated cell proliferation in vitro and arrested tumor growth in fully formed tumors in vivo. We find that LDHB and other related glycolysis genes are specifically upregulated in basal-like/triple-negative breast cancers as compared with other subtypes, suggesting that these tumors are distinctly glycolytic. Consistent with this, triple-negative breast cancer cell lines were more dependent on glycolysis for growth than luminal cell lines. Finally, we find that patients with breast cancer and high LDHB expression in their tumors had a poor clinical outcome. While previous studies have focused on the ubiquitous role of LDHA in tumor metabolism and growth, our data reveal that LDHB is upregulated and required only in certain cancer genotypes. These findings suggest that targeting LDHB or other components of lactate metabolism would be of clinical benefit in triple-negative breast cancer.
Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain ...region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.
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